Effects of supraspinal orphanin FQ/nociceptin

The first reported behavioral action of the endogenous ligand for the "orphan" opioid receptor was a seemingly paradoxical increased sensitivity to nociception (i.e. hyperalgesia) after supraspinal injection into the cerebral ventricles of mice. In the continuing absence of an appropriate in vivo receptor antagonist, studies attempting to define the role of orphanin FQ/nociceptin (OFQ/N) in pain modulation and other behaviors have also featured central injection of peptide. This article reviews the findings of such studies. There appears to be concordance around the observation of anti-opioid actions of supraspinally injected OFQ/N, whereas the observations of hyperalgesia and/or analgesia are much less clear. A portion of the discrepant data may be explained in terms of methodological issues, stress-induced analgesia accompanying experimental protocols, and genotypic variation among subjects. Clarification of OFQ/N's role in nociception, as with other putative biologic functions, will probably depend upon the availability of a selective receptor antagonist.     

A cellular mechanism for the bidirectional pain-modulating actions of orphanin FQ/nociceptin

Orphanin FQ/nociceptin (OFQ/N) and its receptor share substantial structural features and cellular actions with classic opioid peptides and receptors, but have distinct pharmacological profiles and behavioral effects. Currently there is an active debate about whether OFQ/N produces hyperalgesia or analgesia. Using a well-defined brainstem pain-modulating circuit, we show that OFQ/N can cause either an apparent hyperalgesia by antagonizing mu opioid-induced analgesia or a net analgesic effect by reducing the hyperalgesia during opioid abstinence. It presumably produces these two opposite actions by inhibiting two distinct groups of neurons whose activation mediates the two effects of opioid administration. OFQ/N antagonism of the hyperalgesia may have significance for the treatment of opioid withdrawal and sensitized pain.     

FMRFamide-related peptides: anti-opiate transmitters acting in apoptosis

Members of the FMRFamide-related peptide (FaRP) family are neurotransmitters, hormone-like substances and tumor suppressor peptides. In mammals, FaRPs are considered as anti-opiate peptides due to their ability to inhibit opioid signaling. Some FaRPs are asserted to attenuate opiate tolerance. A recently developed chimeric FaRP (Met-enkephalin-FMRFa) mimics the analgesic effects of opiates without the development of opiate-dependence, displaying a future therapeutical potential in pain reduction. In this review we support the notion, that opiates and representative members of the FaRP family show overlapping effects on apoptosis. Binding of FaRPs to opioid receptors or to their own receptors (G-protein linked membrane receptors and acid-sensing ion channels) evokes or suppresses cell death, in a cell- and receptor-type manner. With the dramatically increasing incidence of opiate abuse and addiction, understanding of opioid-induced cell death, and in this context FaRPs will deserve growing attention.     

Endogenous opiates and behavior: 2014

This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (endogenous opioids and receptors), and the roles of these opioid peptides and receptors in pain and analgesia (pain and analgesia); stress and social status (human studies); tolerance and dependence (opioid mediation of other analgesic responses); learning and memory (stress and social status); eating and drinking (stress-induced analgesia); alcohol and drugs of abuse (emotional responses in opioid-mediated behaviors); sexual activity and hormones, pregnancy, development and endocrinology (opioid involvement in stress response regulation); mental illness and mood (tolerance and dependence); seizures and neurologic disorders (learning and memory); electrical-related activity and neurophysiology (opiates and conditioned place preferences (CPP)); general activity and locomotion (eating and drinking); gastrointestinal, renal and hepatic functions (alcohol and drugs of abuse); cardiovascular responses (opiates and ethanol); respiration and thermoregulation (opiates and THC); and immunological responses (opiates and stimulants).This paper is the thirty-seventh consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2014 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (endogenous opioids and receptors), and the roles of these opioid peptides and receptors in pain and analgesia (pain and analgesia); stress and social status (human studies); tolerance and dependence (opioid mediation of other analgesic responses); learning and memory (stress and social status); eating and drinking (stress-induced analgesia); alcohol and drugs of abuse (emotional responses in opioid-mediated behaviors); sexual activity and hormones, pregnancy, development and endocrinology (opioid involvement in stress response regulation); mental illness and mood (tolerance and dependence); seizures and neurologic disorders (learning and memory); electrical-related activity and neurophysiology (opiates and conditioned place preferences (CPP)); general activity and locomotion (eating and drinking); gastrointestinal, renal and hepatic functions (alcohol and drugs of abuse); cardiovascular responses (opiates and ethanol); respiration and thermoregulation (opiates and THC); and immunological responses (opiates and stimulants).     

The effect of opiates and opiate antagonists on heat latency response in the parasitic nematode Ascaris suum

The effects of the opiates morphine and morphine-6-glucuronide (M6G), the mu opioid receptor specific antagonist D-Phe-Cys-Tyr-D-Trp-Om-Thr-Pen-Thr-NH(2) (CTOP), and the general opiate antagonist naloxone on the latency of response to thermal stimulation were determined in the parasitic nematode Ascaris suum. Thermal detection and avoidance behaviors of the worms were evaluated with a tail flick analgesia meter using a modification of a technique employed for nociception experiments in rodents. Morphine and M6G were shown to have a dose dependent analgesic effect on A. suum's latency of response to heat with morphine being the most potent. The analgesic effect of morphine was reversed by naloxone but not CTOP. Neither naloxone nor CTOP was able to block the analgesia of M6G. CTOP but not naloxone had significant analgesic effects on its own. These findings are generally consistent with previous results on the effects of opiates and nitric oxide release from A. suum tissue. Apparently these nematodes possess opioid receptors that effect nociception.     

Nociceptin/orphanin FQ: pain, stress and neural circuits

First isolated some 10 years ago as the endogenous ligand for the "orphan opioid receptor" (ORL-1, now designated NOP), nociceptin/orphanin FQ (N/OFQ) has proved to be a potent inhibitory neuropeptide found across the neuraxis. Because of the homologies between opioids and N/OFQ, functional studies of this peptide have focused most heavily on pain and analgesia. This behavioral literature has been marked by a lack of consistency across laboratories, but much of the data can be explained by considering the potent inhibitory actions of N/OFQ in well-defined modulatory circuits. Presently, the most closely studied such circuit is the rostral ventromedial medulla (RVM), where administration of N/OFQ can block opioid analgesia (by inhibiting opioid-activated pain-inhibiting neurons), but under other conditions produces apparent hypoalgesia (by inhibiting pain-facilitating neurons). The net behavioral effect of N/OFQ in the RVM thus depends on whether experimental conditions are such that the pain-facilitating or pain-inhibiting neurons are active at the time the peptide is given. An important recent finding is that N/OFQ antagonists have antinociceptive properties when given supra-spinally. Although the likelihood of interactions between stress and analgesia systems must be considered in interpreting these data, they suggest that N/OFQ antagonists have potential as clinically useful analgesic drugs.     

孤啡肽在大鼠脑内对抗吗啡镇痛

脑内全新的阿片受体样受体（１９９４）及其内源性配体孤啡肽（１９９５）的发现形成了中枢神经系统阿片／抗阿片相互关系的研究领域中一个新的推动力。基于它们与阿片家族的高同源性及在脑内痛觉整合相关区域的丰富表达,本实验观察了ＯＦＱ在大鼠脑内对吗啡镇痛作用的影响。结果表明：（１）ＯＦＱ可以对抗脑室注射生理盐水引起的镇痛,后者可能是一种由内源性阿片系统介导的应激镇痛。（２）脑室注射ＯＦＱ在很大的剂量范围（４０     

Opioid receptor agonists and Ca2+ modulation in human B cell lines.

Opiates and opioid peptides have been shown to modulate lymphocyte functions; however, little attention has been given to the type of receptors or receptor signaling mechanisms that are involved. Receptor-mediated signaling via ionized free Ca2+ is an event thought to be important in the triggering of lymphocyte activities. We report use of the calcium indicator dye, indo-1, and flow cytometry to identify B lymphocyte calcium responses to physiologic concentrations of opioid peptides. The human B cell lines Nalm 6 and JY responded to the naturally occurring opioid pentapeptide methionine-enkephalin or other opiate receptor agonists with a rapid, dose-dependent rise in free cytoplasmic Ca2+. This opioid peptide effect on Ca2+ modulation was inhibited by the opiate receptor antagonist naloxone. The synthetic enkephalin analogue DAMGO with specificity for mu-type opiate receptors and the synthetic opiate receptor agonists U50,488H and U69,593 with selectivity for kappa-type sites also stimulated calcium responses when applied to the B cell lines. These studies provide evidence that human B cell lines express functional opiate receptors of the mu- and kappa-types and suggest that such receptors, coupled with Ca2+ modulation, are instrumental in the B cell response to opiates and endogenous opioid neuropeptides.     

The next frontier in the molecular biology of the opioid system

The analgesic and euphoric properties of some plant alkaloids such as morphine have been known and exploited for centuries. In contrast, only during the last twenty years have we begun to unravel the molecular basis by which opiates exert their effects, mechanisms important to our general understanding of the nervous system. The analgesic response to opiates is the result of a cascade of biochemical events that are triggered by the interaction of the opiate with specific macromolecular components found on the membranes of nervous system tissues, the opioid receptors. The endogenous ligands of these receptors are small peptides, the opioid peptides. Although much has been learned about the structures and the mode of synthesis of the opioid peptides, little is understood about the structure of their receptors. The application of molecular genetic techniques was of great importance to the studies of the opioid peptides. It is now expected that this same technology will unravel the physical mysteries of the opioid receptors.     

The orphanin FQ/nociceptin gene: structure, tissue distribution of expression and functional implications obtained from knockout mice

Like other neuropeptides, orphanin FQ/nociceptin (OFQ/N) is encoded by a larger precursor protein. The cDNA for the OFQ/N precursor has been cloned from human, rat, mouse and bovine tissue demonstrating that this peptidergic system serves important functions that have been conserved during evolution. The structural organization of the precursor protein is similar to opioid peptide precursors, supporting the view of a common origin for the opioid systems and the OFQ/N system. In addition to OFQ/N, the precursor may encode two other biologically active peptides. Anatomic studies have revealed high levels of expression of the OFQ/N messenger RNA in brain structures involved in sensory, emotional and cognitive processing. In particular, high levels of OFQ/N mRNA were detected in the limbic system, underlining the stress attenuating activities that have been described as an important function of OFQ/N. Recently, mutant mice have been generated that lack the precursor protein of OFQ/N to further define the physiological functions of the OFQ/N system. The OFQ/N-deficient mice are characterized by an increased sensitivity to stressful stimuli and a lack of habituation to chronic and repeated stress. This review will summarize recent findings on the molecular biology of the OFQ/N precursor and relate it to possible physiological functions of this newly discovered neuropeptide system.     

Inhibitory effect of nociceptin on somatostatin secretion of the isolated perfused rat stomach

The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) has recently been isolated from porcine and rat brain and identified as the endogenous ligand of the N/OFQ receptor (NOP). It shows structural similarity with opioid peptides. N/OFQ has also been demonstrated in the gastrointestinal tract, where it inhibits gastrointestinal motility. The effect of N/OFQ on gastric neuroendocrine function is unknown as yet.In the isolated perfused rat stomach, N/OFQ 10(-6) M shows a small, but not significant decrease of basal somatostatin (SRIF) secretion. At the doses of 10(-12) M, 10(-10) and 10(-8) M N/OFQ has neither an effect on basal SRIF nor on basal vasoactive intestinal polypeptide (VIP), gastrin, substance P or bombesin secretion, respectively. However, gastric inhibitory polypeptide (GIP) 10(-9) M prestimulated SRIF secretion is significantly inhibited by N/OFQ 10(-8) M (-45+/-11%; p<0.05 vs. GIP). During concomitant infusion of the specific competitive NOP receptor antagonist [Nphe(1)]nociceptin(1-13)NH(2) 10(-6) M, the effect of N/OFQ is abolished (6+/-11%; p<0.05 vs. GIP and N/OFQ) while the opiate receptor antagonist naloxone 10(-6) M has no significant effect (-32+/-9%; ns vs. GIP and N/OFQ). At the higher concentration of N/OFQ 10(-6) M, the inhibition of prestimulated SRIF secretion (-58+/-6%; p<0.05 vs. GIP) is not influenced by the NOP receptor antagonist at the concentration of 10(-6) M (-49+/-9%; ns vs. GIP and N/OFQ) and 10(-5) M (-69+/-10%; ns vs. GIP and N/OFQ), respectively. On the other hand, infusion of naloxone 10(-6) M attenuates the inhibitory effect of N/OFQ 10(-6) M significantly (-21+/-6%; p<0.05 vs. GIP and N/OFQ).Thus, N/OFQ is an inhibitor of gastric somatostatin secretion. At the lower dose, this effect is transmitted via NOP receptors, while at the higher dose of 10(-6) M, the effect is at least in part mediated via opiate receptors.     

Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: research tools and potential therapeutic agents

The 17-amino acid neuropeptide nociceptin/Orphanin FQ (N/OFQ) was recently identified as the endogenous ligand for the opioid receptor-like (ORL1) receptor, a fourth member of the classical mu, delta, and kappa opioid receptor family. Although ORL1 clearly belongs to the opioid receptor family, it does not bind classical opiates and the ORL1-N/OFQ system has pharmacological actions distinct from the opioid receptor system. This new ligand-receptor system has generated active interest in the opioid community because of its wide distribution and involvement in a myriad of neurological pathways. The past two years have witnessed tremendous advances in the design and discovery of very potent and selective peptide and nonpeptide agonist and antagonist ligands at ORL1. These discoveries have facilitated the understanding of the role of the ORL1-N/OFQ system in a variety of processes such as pain modulation, anxiety, food intake, learning, memory, neurotransmitter release, reward pathways, and tolerance development. The ORL1 receptor therefore represents a new molecular target for the design of novel agents for anxiety, analgesia, and drug addiction. Indeed, there is tremendous interest in the pharmaceutical industry in the development of nonpeptide ligands such as the potent ORL1 agonist, Ro 64-6198, as anxiolytics and the ORL1 antagonist JTC-801 as novel analgesics. This review presents an overview of the various peptide and nonpeptide ORL1 ligands with an emphasis on their potential therapeutic utility in various human disorders.     

On the specificity of naloxone as an opiate antagonist.

Since the discovery of endogenous opioid peptides in brain (68,69,97,113, 128) and the pituitary gland (26,81,105,125) there has been considerable interest in their possible roles in a variety of physiological and pharmacological processes. Many studies have used antagonism by naloxone as a criterion for implicating endogenous opiates in a process, assuming that naloxene has no pharmacological actions other than those related to blockade of opiate receptors. The doses of naloxene used are often higher than those required to antagonize the analgesic and other effects of morphine. However, multiple forms of opiate receptors are present in nervous tissue and higher concentrations of naloxene are required to antagonize effects mediated by some of these receptors (83). Although the earlier literature supports the assumption that the effects of naloxene are due to the blockade of opiate receptors (87), there are an increasing number of reports which indicate that naloxene may have pharmacological actions unrelated to opiate receptor blockade. The subsequent review serves to emphasize that antagonism by naloxene is a necessary but not sufficient criterion for invoking the mediation of a response by an endogenous opiate (61). Additional lines of evidence which serve to strengthen the conclusion that endogenous opiates mediate a process will be considered.     

Neurohumoral effects of orphanin FQ/nociceptin: relevance to cardiovascular and renal function

Orphanin FQ/Nociceptin (OFQ/N) is a peptide whose structure resembles that of the endogenous opioid peptides (endorphins). OFQ/N and its receptor are distributed in neural tissue and brain regions involved in the regulation of pituitary hormone release. Functional studies have shown that this peptide evokes a unique pattern of cardiovascular and renal excretory responses. This review will focus on the neural and humoral effects of OFQ/N and how this peptide may participate in the regulation of cardiovascular and renal function.     

Orphanin FQ/nociceptin: from neural circuitry to behavior

Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand for the "orphan" opioid receptor ORL-1 (NOP(1)) was first identified in 1995. In the years since its discovery, a large body of evidence has accumulated showing that OFQ/N and its receptor are widely distributed in the nervous system, and showing that OFQ/N has potent and indiscriminate inhibitory actions on neurons in many regions. However, numerous studies investigating the functional role of OFQ/N in physiology or behavior have failed to provide a coherent view. Pain and analgesia have been the best studied, and administration of OFQ/N is reported to have no effect, to produce hyperalgesia, analgesia or anti-hyperalgesia. Effects of OFQ/N receptor antagonists have proved similarly contentious. In an attempt to resolve this controversy, we investigated the actions of OFQ/N on the activity of physiologically characterized neurons in the rostral ventromedial medulla, a region with a well-documented role in pain modulation(Heinricher et al., 1997). The results of those experiments demonstrate that this peptide is neither "anti-opioid" or "anti-hyperalgesic". It is simply inhibitory. For this reason, the effects seen in functional studies will only be fully understood when examined in the context of identified neural circuits.     

Butorphanol tartrate induces feeding in rats

Peripheral administration of butorphanol tartrate markedly enhanced feeding from 0800 to 1400 hours when compared with vehicle controls. Butorphanol tartrate feeding was not antagonized by doses of naloxone as high as 10 mg/kg. These data support the concept that the kappa or sigma opiate receptors are involved in feeding behavior.It is well recognized that the endogenous opiates play a role in the central regulation of appetite (1, 2, 3, 4). Numerous studies have shown that The endogenous opioid peptides and morphine can initiate feeding under various conditions (5–12) whereas the opiate antagonist, naloxine can reduce food consumption (13–20). Recently, the endogenous opiod peptide, dynorphin, has been reported to enhance food intake (12–25).Much evidence has been accumulated indicating that a number of opiate receptors are present in the brain, each one having a high affinity for a specific endogenous opioid peptide (26, 27). Both the cyclazocine related compounds (28) and the feeding enhancer, dynorphin (29–32), have been reported to be specific kappa receptor agonists. In the present study, we report on the effect of the morphinan congener, butorphanol tartrate (33), on ingestive behaviour.     

IgG from antiserum against endogenous mammalian FMRF-NH2-related peptides augments morphine- and stress-induced analgesia in mice

Two mammalian FMRF-NH2-like peptides have been isolated from bovine brain; an octapeptide with the structure Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (F-8-F-NH2) and an octadecapeptide, Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe- NH2 (A-18-F-NH2). In the present study determinations were made of the effects of intracerebroventricular administration of IgG prepared from antisera raised against these peptides on nociception and morphine- and immobilization-induced opioid analgesia in mice. Both F-8-F-NH2-IgG and A-18-F-NH2-IgG antisera increased nociception (thermal response latency) and significantly augmented morphine- and immobilization-induced analgesia in a naloxone reversible manner, with F-8-F-NH2-IgG antisera having a greater effect than A-18-F-NH2-IgG antisera. These results provide further evidence that mammalian FMRF-NH2-like peptides function as endogenous opiate antagonists and have a role in the mediation of antinociception.     

孤啡肽（OFQ）的分布,特性及其可能作用

孤啡肽是１９９５年底新发现的一种结构与内阿片肽类似的物质,它的发现引发了国际上相关研究的热潮。近年来的研究已经基本阐明了孤啡肽在中枢及外周的分布及其生化与药理特性,并初步发现该物质参与痛觉调制、影响运动与行为、调控递质释放,还可能参与情绪反应与学习记忆、神经内分泌与免疫过程以及胃的活动等,但其确切作用仍有待于进一步阐明。     

Social conflict activates opioid analgesic and ingestive behaviors in male mice

The activation of endogenous opioid mechanisms and their subsequent effects on rodent behavior and physiology has usually been characterized following artificial stress. In this study the more naturalistic stress arising from social conflict between male mice was used to investigate the involvement of opioid systems in post-conflict analgesic and ingestive behaviors. Both the aggressive encounters and the subsequent defeat experience resulted in marked analgesia and the induction of ingestive behaviors. Feeding and drinking responses were analogous to those observed after administrations of either the endogenous opioid peptide, β-endorphin, or the exogenous opioid agonist morphine. The ingestive behaviors following defeat or central opiate administration were blocked by the opiate antagonist naloxone. The present results support the hypothesis of a direct activation of the endogenous opiate system following social conflict.     

Nocistatin: a novel neuropeptide encoded by the gene for the nociceptin/orphanin FQ precursor

We identified a novel neuropeptide and named it "nocistatin." Its presence was expected by analysis of the precursor for the neuropeptide nociceptin or orphanin FQ (Noc/OFQ), previously identified as an endogenous ligand for the orphan opioid receptor-like receptor. The precursor prepronociceptin/orphanin FQ (ppNoc/OFQ) comprises at least two bioactive peptides, nocistatin and Noc/OFQ. Noc/OFQ is involved in a broad range of pharmacological actions in various tissues from the central nervous system to the periphery. In pain transmission, Noc/OFQ is reported to have different effects including nociception, no effect, and analgesia, depending on the animal species tested, doses, route of administration, and so on. We found that intrathecal administration of Noc/OFQ induced pain responses including allodynia and hyperalgesia. Simultaneous administration of nocistatin blocked the allodynia and hyperalgesia induced by Noc/OFQ, whereas anti-nocistatin antibody decreased the threshold for the Noc/OFQ-induced allodynia. The endogenous heptadecapeptide nocistatin was isolated from bovine brains and recently identified in mouse, rat, and human brain and in human cerebrospinal fluid. Although human, rat and mouse ppNoc/OFQ produced larger respective counterparts with 30, 35, and 41 amino acid residues, all peptides showed the antinociceptive activity. This activity was ascribed to the carboxyl-terminal hexapeptide of nocistatin, Glu-Gln-Lys-Gln-Leu-Gln, which is conserved beyond species. Nocistatin also attenuated the allodynia and hyperalgesia evoked by prostaglandin E(2) and the inflammatory hyperalgesia induced by formalin or carrageenan/kaolin, and reversed the Noc/OFQ-induced inhibition of morphine analgesia at picogram doses. Furthermore, nocistatin counteracted the impairment of learning and memory induced by Noc/OFQ or scopolamine. Nocistatin is widely present in the spinal cord and brain. Although nocistatin did not bind to the Noc/OFQ receptor, it bound to the membrane of mouse brain and spinal cord with a high affinity. Nocistatin is a novel bioactive peptide produced from the same precursor as Noc/OFQ, and it plays important roles in the regulation of pain transmission and learning and memory processes in the central nervous system.